Conformationally rigid aryl prostaglandins for use in glaucoma therapy

ABSTRACT

Conformationally rigid aryl prostaglandins are useful in the treatment of glaucoma and ocular hypertension. Also disclosed are ophthalmic pharmaceutical compositions comprising said prostaglandins.

This application is a 371 of PCT/US96/17901 filed Nov. 12, 1996 which isa CIP of 08/480,707 filed Jun. 7, 1995 now U.S. Pat. No. 5,698,733.

BACKGROUND OF THE INVENTION

The present invention relates to the use of prostaglandins andprostaglandin analogues for the treatment of glaucoma and ocularhypertension. As used herein, the terms “prostaglandin” and “PG” shallrefer to prostaglandins and derivatives and analogues thereof, except asotherwise indicated by context.

Naturally-occurring prostaglandins, especially prostaglandins of the Fseries (such as PGF_(2α) and the E series (such as PGE₂), are known tolower intraocular pressure (IOP) after topical ocular instillation, butcan cause conjunctival hyperemia and/or edema as well as inflammation.Many synthetic prostaglandins have been observed to lower intraocularpressure, but most such compounds also produce the aforementioned sideeffects which significantly limit their clinical utility.

Various attempts have been made to overcome these well-knownside-effects. Some have synthesized derivatives of naturally-occurringprostaglandins in an attempt to design out selectively the side effectswhile maintaining the IOP-lowering effect. See, e.g., Stjernschantz etal. (U.S. Pat. Nos. 5,422,368 and 5,321,128), Woodward et al. (U.S. Pat.No. 5,093,329), Chan et al. (WO 92/08465 and U.S. Pat. No. 5,446,041).Others, including Ueno et al. (EP 330 511 A2) and Wheeler (EP 435 682A2) have tried complexing prostaglandins with various cyclodextrins.

SUMMARY OF THE INVENTION

It has now been unexpectedly discovered that certain conformationallyrigid analogues of PGF_(2α) will lower or control IOP with no orsignificantly reduced side effects of conjunctival hyperemia and/oredema. An agent which exhibits comparable efficacy, but with reducedside effects when compared to other agents, is said to have an improvedtherapeutic profile.

While bound by no theories, it is believed that increased conformationalrigidity resulting from the presence of a bicyclic ring at the terminusof the omega chain of the prostaglandins of the present invention allowsincreased discrimination amongst the various PG receptors, which, inturn, allows a higher separation of desirable and undesirableactivities, and therefore an improved therapeutic profile.

DETAILED DESCRIPTION OF THE INVENTION

The conformationally rigid aryl prostaglandins which are useful in thecompositions of the present invention have the general formula (I):

wherein:

Y═C(O)NR₁R₂, CH₂OR₃, CH₂NR₁R₂, CO₂R₁, CO₂M, where M is a cationic saltmoiety;

R₁, R₂ (same or different)═H, C₁-C₆ alkyl or alkenyl, or C₃-C₆cycloalkyl;

R, R₃ (same or different)═C(O)R₄, or H, where R₄═C₁-C₆ alkyl or alkenyl,or C₃-C₆ cycloalkyl;

A═CH₂CH₂, cis or trans CH═CH, or C≡C;

Z═CH₂CH₂, trans CH═CH;

X═O, S(O)_(n), (CH₂)_(n), or CH₂O, where n=0, 1, or 2;

B═H and OH in either configuration, or a double bonded O;

D═R₁, OR₁, halogen, S(O)_(n)R₄, NO₂, NR₁R₂, or CF₃, where n=0, 1, or 2,and R₁, R₂, and

R₄ are as defined above; and

m=0, 1, or 2.

Most preferred compounds include:

II. (5Z, 13E)-(9S, 11R, 15S)-15-(2-indanyl)-9, 11, 15-trihydroxy-16, 17,18, 19, 20-pentanor-5, 13-prostadienoic acid isopropyl ester.

III. (5Z)-(9S, 11R, 15R)-15-(2-indanyl)-9, 11, 15-trihydroxy-16, 17, 18,19, 20-pentanor-5-prostenoic acid isopropyl ester.

IV. (5Z, 13E)-(9S, 11R,15S)-15-(2R-(1,2,3,4-tetrahydronaphthyl))-trihydroxy-16, 17, 18, 19,20-pentanor-5, 13-prostadienoic acid isopropyl ester.

V. (5Z, 13E)-(9S, 11R, 15S)-15-(2S-(1,2,3,4-tetrahydronaphthyl))-9, 11,15-trihydroxy-16, 17, 18, 19, 20-pentanor-5, 13-prostadienoic acidisopropyl ester.

VI. (5Z, 13E)-(9S, 11R, 15R)-15-(2-benzo[b]furyl)-9, 11,15-trihydroxy-16, 17, 18, 19, 20-pentanor-5, 13-prostadienoic acidisopropyl ester.

VII. (5Z, 13E)-(9S, 11R, 15R)-15-(2R-(2,3-dihydrobenzo[b]furyl)-9, 11,15-trihydroxy-16, 17, 18, 19, 20-pentanor-5, 13-prostadienoic acidisopropyl ester.

VIII. (5Z, 13E)-(9S, 11R, 15R)-15-(2S-(2,3-dihydrobenzo[b]furyl)-9, 11,15-trihydroxy-16, 17, 18, 19, 20-pentanor-5, 13-prostadienoic acidisopropyl ester.

IX. (5Z, 13E)-(9R, 11R,15R)-15-(2R-[3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl)-9, 11,15-trihydroxy-16, 17, 18, 19, 20-pentanor-5, 13-prostadienoic acidisopropyl ester.

X. (5Z, 13E)-(9S, 11R,15R)-15-(2S-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl)-9, 11,15-trihydroxy-16, 17, 18, 19, 20-pentanor-5,13-prostadienoic acidisopropyl ester.

Some of the above-mentioned prostaglandins are disclosed in U.S. Pat.No. 4,152,527 (Hess et al.) issued on May 1, 1979, and in Hyashi, M., etal., J. Med. Chem. 23:519 (1980). To the extent that U.S. Pat. No.4,152,527 discloses the synthesis of the prostaglandins of the presentinvention, that patent is incorporated by reference herein.

The compounds of formula (I) wherein Z═CH₂CH₂ (and the otherconstituents are as defined above) are believed to be novel. Thepreferred novel PGF_(2α) derivatives include those novel compounds offormula (I) wherein: X═CH₂ and A═CH₂CH₂, or cis CH═CH.

The compounds of formula (I) can be prepared by generally employing themethods disclosed in the foregoing references or in the followingexample. The following synthesis is representative of those which may beused to prepare compounds of the present invention. Those skilled in theart will appreciate the modifications to the synthesis of Example 1necessary to yield such compounds.

In the foregoing illustrations, as well as those provided hereinafter, ahatched line, as used e.g. at carbon 9, indicates the α configuration. Asolid triangular line indicates the β configuration. Dashed lines onbonds indicate a single or double bond. Two solid lines between carbonsindicate a double bond of the specified configuration.

In the Example 1 which follows, the following standard abbreviations areused: g=grams (mg=milligrams); mol=moles (mmol=millimoles);mL=milliliters; mm Hg=millimeters of mercury; mp=melting point;bp=boiling point; h=hours; and min=minutes. In addition, “NMR” refers tonuclear magnetic resonance spectroscopy and “MS” refers to massspectrometry.

EXAMPLE 1

Synthesis of (5Z)-(9S, 11R, 15R)-15-(2-indanyl)-9, 11, 15-trihydroxy-16,17, 18, 19, 20-pentanor-5-prostenoic acid isopropyl ester (III).

A:[3aR, 4R(1E, 3R), 5R,6aS]-4-[3-hydroxy-3-(2-indanyl)propyl]-5-hydroxy-hexahydro-2H-cyclopental[b]furan-2-one(2)

A solution of olefin 1 (0.7g, 2.2 mmol) [synthesis described in: J. Med.Chem. 26:328 (1983)] in 10 mL of a 1:1 v:v mixture of methanol:ethylacetate was hydrogenated in the presence of 10% Pd/C (50mg) at 40 psi ina Parr hydrogenation apparatus for 1h. The mixture was filtered throughCelite 521 and concentrated to afford 2, which was used in the next stepwithout further purification.

B: [3aR, 4R(1E,3R), 5R,6aS]-4-[3-(2-indanyl)-3-(tetrahydropyran-2-yloxy)propyl]-5-(tetrahydropyran-2-yloxy)-hexahydro-2H-cyclopenta[b]furan-2-one(3)

Compound 2 from above was dissolved in CH₂Cl₂ (30mL) and the mixture wascooled to 0° C. 3,4-Dihydro-2H-pyran was added (0.42 g, 5.0 mmol),followed by p-toluenesulfonic acid monohydrate (50mg, 0.2 mmol). Thesolution was stirred at room temperature for 2h, poured into saturatedaqueous NaHCO₃, and extracted with CH₂Cl₂. The solution was dried overMgSO₄, filtered, and concentrated, and the residue was chromatographedon Silica Gel 60 (230-400 mesh ASTM) to afford 0.4 g (36%) of 3 as aviscous oil. ¹H NMR (CDCl₃) δ7.2 (m, 4H), 5.0 (m, 1H), 4.7 (m, 2H), 4.1(m, 1H), 3.9-3.6 (m, 3H), 3.5 (m, 2H), 3.2-2.5 (bm, 8H), 2.4-2.0 (m,1H), 1.8-1.3(m, 18H).

C: (5Z)-(9S, 11R,15R)-11,15-bis(tetrahydropyran-2-yloxy)-9-hydroxy-15-(2-indanyl)-16,17,18,19,20-pentanor-5-prostenoicacid isopropyl ester (4)

To a −78° C. solution of lactone 3 (0.4 g, 0.8 mmol) in toluene (10 mL)was added a 1.5 M solution of DIBAL-H in hexane (1 mL, 1 mmol). Afterstirring for 2 h at 0° C., isopropanol (0.2 mL) was added, the mixturewas poured into a solution of sodium potassium tartrate, extracted withethyl acetate (2×50 mL), dried (MgSO₄), and concentrated to afford 0.21g (52%) of crude lactol.

To a solution of (4-carboxybutyl)triphenylphosphonium bromide (0.13 g,0.3 mmol) in DMSO (6 mL) was added a DMSO solution of sodiummethylsulfinylmethide (0.6 mmol, 0.2 M in DMSO). To the mixture wasadded dropwise a solution of the above lactol (0.15 g, 0.3 mmol) in DMSO(3 mL). The solution was stirred for 16 h at 50° C., cooled to roomtemperature, and quenched by the addition of 10% aqueous citric acid topH 5.5. The mixture was extracted with ethyl acetate, dried (MgSO₄),filtered, and concentrated.

The crude acid (0.2g, 0.4 mmol) was dissolved in acetone (20 mL) andtreated with DBU (0.15 g, 1.0 mmol) and 2-iodopropane (0.17g, 1.0 mmol)for 16h at 23° C., then poured into water and extracted with ether (2×50mL). The residue was purified by flash chromatography on Silica Gel 60(230-400 mesh ASTM) with 3:1 hexanes:ethyl acetate to furnish 0.175 g(71%) of the isopropyl ester 4. PMR (CDCl₃) δ7.13 (m, 4H), 5.4 (m, 2H),4.7 (m, 2H), 5.0 (hept, J=6.3 Hz, 1H), 4.8-4.6 (m, 2H), 4.1-3.6 (m, 5H),3.5(m, 2H), 3.1-2.7 (6m, 4H), 2.3 (t, 2H), 2.1 (m, 2H), 1.9-1.2 (bm,29H), 1.2 (d, J=6.3 Hz, 6H).

D: (5Z)-(9S,11R,15R)-15-(2-indanyl)-9, 11, 15-trihydroxy-16, 17, 18, 19,20-pentanor-5-prostenoic acid isopropyl ester (III)

The isopropyl ester, 4, (0.10 g, 0.16 mmol) was dissolved in aceticacid/THF/H₂O (4:2:1) and stirred at 50° C. for 30 min., then stirred at23° C. for 16h. The solution was poured into a saturated aqueous NaHCO₃solution and extracted with ethyl acetate (1×50 mL) and ether (1×50 mL)sequentially. The combined organic extracts were washed with water,dried over MgSO₄, filtered and concentrated in-vacuo. The residue waspurified by flash chromatography on Silica Gel 60 (230-400 mesh ASTM)with a 3:1 mixture of ethyl acetate:hexanes as element. This yielded0.017 g (20%) of III as a pale yellow oil. PMR (CDCl₃) δ7.1 (m, 4H) 5.4(m, 2H), 4.9 (hept, J=6.3 Hz, 1H), 4.2 (m,1H), 3.9 (m, 1H), 3.6 (m, 1H),3.1-2.6 (bm, 5H), 2.3-1.9 (bm, 10H), 1.8-1.3 (bm, 10H), 1.1 (d, J=6.3Hz, 6H), CMR (CDCl₃) δ173.46, 143.01, 142.85, 129.63, 129.33, 126.24,126.91, 124.47, 124.34, 78.81, 75.26, 74.73, 67.66, 52.91, 52.00, 46.08,42.59, 35.85, 35.39, 34.25, 34.04, 29.77, 26.90, 26.64, 24.93, 21.84.

The conformationally rigid prostaglandins of the present invention maybe formulated in various pharmaceutical compositions for administeringto humans and other mammals as a treatment of glaucoma or ocularhypertension. As used herein, the term “pharmaceutically effectiveamount” refers to that amount of a compound of the present inventionwhich lowers IOP when administered to a patient, especially a mammal.The preferred route of administration is topical. The compounds of thepresent invention may be administered as solutions, suspensions, oremulsions (dispersions) in an ophthalmically acceptable vehicle. As usedherein, the term “ophthalmically acceptable vehicle” refers to anysubstance or combination of substances which are effectivelynon-reactive with the compounds and suitable for administration to apatient. Stabilizers and/or solubilizers are not considered to bereactive substances. Preferred are aqueous vehicles suitable for topicalapplication to the patient's eyes.

The compounds of the present invention are preferably administeredtopically. The dosage range is generally between about 0.01 and about1000 micrograms per eye (μg/eye) and is preferably between about 0.1 and100 μg/eye. In forming compositions for topical administration, thecompounds of the present invention are generally formulated as betweenabout 0.001 to about 1.0 percent by weight (wt %) solutions in water ata pH between about 4.5 to 8.0 and preferably between about 7.0 and 7.5.The compounds are preferably formulated as between about 0.0001 to about0.1 wt % and, most preferably, between about 0.001 and about 0.02 wt %.While the precise regimen is left to the discretion of the clinician, itis recommended that the resulting solution be topically applied byplacing one drop in each eye one or two times a day.

Other ingredients which may be desirable to use in the ophthalmicpreparations of the present invention include preservatives, co-solventsand viscosity building agents.

Antimicrobial Preservatives

Ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethylalcohol, edetate disodium, sorbic acid, Onamer M, or other agents knownto those skilled in the art. Such preservatives are typically employedat a level between about 0.001% and about 1.0% by weight.

Co-Solvents

Prostaglandins, and particularly ester derivatives, typically havelimited solubility in water and therefore may require a surfactant orother appropriate co-solvent in the composition. Such co-solventsinclude: Polysorbate 20, 60 and 80; Pluronic F-68, F-84 and P-103;cyclodextrin; CREMOPHORE® EL (polyoxyl 35 castor oil); or other agentsknown to those skilled in the art. Such co-solvents are typicallyemployed at a level between about 0.01% and about 2% by weight.

Viscosity Agents

Viscosity greater than that of simple aqueous solutions may be desirableto increase ocular absorption of the active compound, to decreasevariability in dispensing the formulations, to decrease physicalseparation of components of a suspension or emulsion of formulationand/or otherwise to improve the ophthalmic formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, combinations of the foregoing, and other agents known tothose skilled in the art. Such agents are typically employed at a levelbetween about 0.01% and about 2% by weight.

The following examples are representative pharmaceutical compositions ofthe invention for topical use in lowering of intraocular pressure.

EXAMPLE 2

The following formulations A-E are representative pharmaceuticalcompositions of the invention for topical use in lowering of intraocularpressure. Each of formulations A through E may be formulated inaccordance with procedures known to those skilled in the art.

FORMULATION A Ingredient Amount (wt %) Compound of formula II 0.003Dextran 70 0.1 Hydroxypropyl methylcellulose 0.3 Sodium Chloride 0.77Potassium chloride 0.12 Disodium EDTA (Edetate disodium) 0.05Benzalkonium chloride 0.01 HCl and/or NaOH pH 7.2-7.5 Purified waterq.s. to 100%

FORMULATION B Ingredient Amount (wt %) Compound of formula III 0.001Monobasic sodium phosphate 0.05 Dibasic sodium phosphate (anhydrous)0.15 Sodium chloride 0.75 Disodium EDTA (Edetate disodium) 0.01Benzalkonium chloride 0.02 Polysorbate 80 0.15 HCl and/or NaOH pH7.3-7.4 Purified water q.s. to 100%

FORMULATION C Ingredient Amount (wt %) Compound of formula III 0.001Dextran 70 0.1 Hydroxypropyl methylcellulose 0.5 Monobasic sodiumphosphate 0.05 Dibasic sodium phosphate (anhydrous) 0.15 Sodium chloride0.75 Disodium EDTA (Edetate disodium) 0.05 Benzalkonium chloride 0.01NaOH and/or HCl pH 7.3-7.4 Purified water q.s. to 100%

FORMULATION D Ingredient Amount (wt %) Compound of formula II 0.003Monobasic sodium phosphate 0.05 Dibasic sodium phosphate (anhydrous)0.15 Sodium chloride 0.75 Disodium EDTA (Edetate disodium) 0.05Benzalkonium chloride 0.01 HCl and/or NaOH pH 7.3-7.4 Purified waterq.s. to 100%

FORMULATION E Ingredient Amount (wt/vol %) Compound of formula II 0.01Polyoxyl 35 castor oil 0.1 Tromethamine 0.12 Boric acid 0.3 Mannitol 4.6Disodium EDTA (edetate disodium) 0.1 Benzalkonium Chloride Solution 0.01HCl and/or NaOH pH 7.3-7.4 Purified Water q.s. to 100%

EXAMPLE 3

In the present study compounds II and III, and PGF_(2α) isopropyl ester(PGF_(2α)iPr) were tested for ocular irritation in the New Zealand (NZA)rabbit. Prostaglandins were dosed as 1.0 microgram of compound pertreatment in 30 μL of test formulation. Conjunctival hyperemia, swellingand discharge were evaluated using a system devised to grossly comparethe irritation potential of prostaglandins in the NZA rabbit. Using theHackett/McDonald scoring system (Hackett, R. B. and McDonald, T. O. “EyeIrritation” in Dermatotoxicology, 4th edition, Marzulli, F. N. andMaibach, H. I. editors, Hemisphere Publishing Corp., Washington D.C.(1991)), conjunctival hyperemia, conjunctival swelling, and oculardischarge were graded using a slit-lamp prior to compound instillationand 1, 2, 3, and 5 hours after topical ocular instillation of the testcompounds. The percentage of eyes scoring +2 or greater for all timepoints was calculated for each parameter (conjunctival hyperemia,conjunctival swelling, and ocular discharge). To facilitate comparison,PGF_(2α)iPr was administered at the same time as the test agent. Thecumulative results are presented in Table 1.

TABLE 1 % Incidence Number Conjunctival Compound of Animals HyperemiaSwelling Discharge II 10  0  0  5 PGF_(2α) iPr  8 69 59 69 III 10  0  0 0 PGF_(2α) iPr 10 48 18 13

Discussion

It is evident from Table 1 that the conformationally rigid analogs ofPGF_(2α) isopropyl ester, compounds II and III, produced a low incidenceof ocular irritation in the rabbit compared to PGF_(2α) isopropyl ester,which caused a relatively high incidence of hyperemia, conjunctivalswelling and discharge. This indicates that the structural modificationpresent in compounds II and III attenuates the ocular side effectsassociated with the PGF_(2α) isopropyl ester.

EXAMPLE 4

In the study presented below, compounds II and III, and PGF_(2α)isopropyl ester (PGF_(2α) iPr) were tested for IOP-lowering effect incynomologus monkey eyes. The right eyes of the cynomologus monkeys inthis study were previously given laser trabeculoplasty to induce ocularhypertension in the lasered eye. Animals had been trained to sit inrestraint chairs and conditioned to accept experimental procedureswithout chemical restraint. IOP was determined with a pneumatonometerafter light corneal anesthesia with dilute proparacaine. The testprotocol included a five-dose b.i.d. treatment regimen because of thetypical delayed response to prostaglandins. The test formulations wereadministered to the lasered right eyes, and the normal left eyesremained untreated for compounds II and III, or to both eyes forPGF_(2α) isopropyl ester (PGF_(2α)iPr). Baseline IOP values weredetermined prior to treatment with the test formulation, and IOP wasdetermined 16 hours after the fourth dose for all compounds, 2, 4, and 6hours after the fifth dose for compounds II and III, and 1, 3 and 7hours after the fifth dose for PGF_(2α)iPr. Results are presented inTable 2 as the mean percent reduction of IOP from baseline +/− SEM.Prostaglandins were dosed as 1.0 microgram of compound per treatment in30 μL of test formulation.

TABLE 2 Number Baseline of IOP (mm Percent IOP Reduction +/− SEM (Hoursafter Last Dose/Dose #) Compound Animals Hg) 16/4 1/5 2/5 3/5 4/5 6/57/5 II 9 37.9 20.9 +/− 4.1 16.3 +/− 5.1 24.2 +/− 5.8 27.4 +/− 5.9 III 943.7 11.4 +/− 4.0 20.3 +/− 4.6   24 +/− 4.5   15 +/− 5.0 PGF_(2α) iPr 434.8  5.8 +/− 4.0 27.6 +/− 14.4 38 +/− 11.7 25.6 +/− 14.4

Discussion

Table 2 shows that the conformationally rigid analogs of PGF_(2α)isopropyl ester, compounds II and III, produce a significant degree ofIOP reduction for the time period tested. Thus, the conformationallyrigid compounds II and III, with their low incidence of side effects(Example 3), exhibit a significantly improved therapeutic profile overPGF_(2α) isopropyl ester.

The invention has been described by reference to certain preferredembodiments however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspirit or essential characteristics. The embodiments described above aretherefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description.

What is claimed is:
 1. A method of treating glaucoma and ocularhypertension which comprises topically administering to the affected eyea therapeutically effective amount of a compound of formula (I)

wherein: Y═C(O)NR₁R₂, CH₂OR₃, CH₂NR₁R₂, CO₂R₁, or CO₂M, where M is acationic salt moiety; R₁, R₂(same or different)═H, C₁-C₆ alkyl oralkenyl, or C₃-C₆ cycloalkyl; R, R₃(same or different)═C(O)R₄ or H,where R₄═C₁-C₆ alkyl or alkenyl, or C₃-C₆ cycloalkyl; A═CH₂CH₂, cis ortrans CH═CH, or C≡C; Z═CH₂CH₂ or trans CH═CH; X═[O, S(O)_(n),](CH₂)_(n),where n=0, 1, or 2; B═H and OH in either configuration or double bondedO; D═R₁, OR₁, halogen, S(O)_(n)R₄, NO₂, NR₁R₂, H, or CF₃, where n=0, 1,or 2, and R₁, R₂ and R₄ are as defined above; and m=0, 1,or
 2. 2. Themethod of claim 1, wherein: Y═CO₂R₁, where R₁═H, C₁-C₆ alkyl or alkenyl,or C₃-C₆ cycloalkyl; R═C(O)R₄ or H, where R₄═C₁-C₆ alkyl or alkenyl, orC₃-C₆ cycloalkyl; A═CH₂CH₂, cis or trans CH═CH, or C≡C; Z═CH₂CH₂ ortrans CH═CH; X═[O or] CH₂; B═H and OH in either configuration; and D═R₁,OR₁, halogen, or H, where R₁ is as defined above.
 3. The method of claim2, wherein: Y═CO₂R₁, where R₁═C₃ alkyl in the isopropyl form; R═H;A═CH₂CH₂ or cis CH═CH; Z═CH₂CH₂ or trans CH═CH; X═CH₂; B—β═H and α—OH;and D═H.
 4. The method of claim 1, wherein between about 0.01 and about1000 micrograms of the compound is administered.
 5. The method of claim4, wherein between about 0.1 and about 100 micrograms of the compound isadministered.
 6. A topical ophthalmic composition for the treatment ofglaucoma and ocular hypertension, said composition comprising anophthalmically acceptable vehicle and a therapeutically effective amountof a compound of formula (I):

wherein: Y═C(O)NR₁R₂, CH₂OR₃, CH₂NR₁R₂, CO₂R₁, or CO₂M, where M is acationic salt moiety; R₁, R₂(same or different)═H, C₁-C₆ alkyl oralkenyl, or C₃-C₆ cycloalkyl; R, R₃(same or different)═C(O)R₄ or H,where R₄═C₁-C₆ alkyl or alkenyl, or C₃-C₆ cycloalkyl; A═CH₂CH₂, cis ortrans CH═CH, or C≡C; Z═CH₂CH₂, or trans CH═CH; X═[O, S(O)_(n),or](CH₂)_(n), where n=0, 1 or 2; B═H and OH in either configuration ordouble bonded O; D═R₁, OR₁, halogen, S(O)_(n)R₄, NO₂, NR₁R₂, H, or CF₃,where n=0, 1, or 2, and R₁, R₂ and R₄ are as defined above; and m=0, 1,or
 2. 7. The composition of claim 6, wherein: Y═CO₂R₁, where R₁═H, C₁-C₆alkyl or alkenyl, or C₃-C₆ cycloalkyl; R═C(O)R₄ or H, where R₄═C₁-C₆alkyl or alkenyl, or C₃-C₆ cycloalkyl; A═CH₂CH₂, cis or trans CH═CH, orC≡C; Z═CH₂CH₂, or trans CH═CH; [X═O] X═(CH₂)_(n), where n=1 or 2; B═Hand OH in either configuration; and D═R₁, OR₁, halogen, or H, where R₁is as defined above.
 8. The composition of claim 7, wherein: Y═CO₂R₁,where R₁═C₃ alkyl in the isopropyl form; R═H; A═CH₂CH₂ or cis CH═CH;Z═CH₂CH₂ or trans CH═CH; X═[O or] CH₂; β—H and α—OH; and D═H.
 9. Thecomposition of claim 8, wherein Z═CH₂CH₂.
 10. The composition of claim6, wherein the compound is present at a concentration between about0.0001 and about 5 percent by weight.
 11. The composition of claim 9,wherein the compound is present at a concentration between about 0.001and about 1 percent by weight.